FDA

Rezurock

Approved 16 Jul 2021OralTablet

Indications

REZUROCK is indicated for the treatment of adult and pediatric patients 12 years and older with chronic graft-versus-host disease (chronic GVHD) after failure of at least two prior lines of systemic therapy. REZUROCK is a kinase inhibitor indicated for the treatment of adult and pediatric patients 12 years and older with chronic graft-versus-host disease (chronic GVHD) after failure of at least two prior lines of systemic therapy.

( 1 )

Contraindications

None. None. ( 4 )

Warnings and precautions

Embryo-Fetal Toxicity : Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.1 , 8.1 , 8.3 )

5.1Embryo-Fetal Toxicity Based

on findings in animals and its mechanism of action, REZUROCK can cause fetal harm when administered to a pregnant woman. In animal reproduction studies, administration of belumosudil to pregnant rats and rabbits during the period of organogenesis caused adverse developmental outcomes including embryo-fetal mortality and malformations at maternal exposures (AUC) less than those in patients at the recommended dose. Advise pregnant women of the potential risk to a fetus.

Advise females of reproductive potential and males with female partners of reproductive potential to use effective contraception during treatment with REZUROCK and for one week after the last dose [see Use in Specific Populations (8.1 , 8.3) , Nonclinical Toxicology (13.1) ] .

Interactions

Strong CYP3A Inducers : Increase REZUROCK dosage to 200 mg twice daily. ( 7.1 , 2.3 ) Proton Pump Inhibitors : Increase REZUROCK dosage to 200 mg twice daily. ( 7.1 , 2.3 ) BCRP Substrates: Avoid concomitant use with drugs that are BCRP substrates where possible. If used together, monitor patients more frequently for adverse reactions and decrease the substrates dosage(s) in accordance with the respective Prescribing Information.

( 7.2 ) OATP1B1 Substrates: If used together, monitor patients more frequently for adverse reactions and decrease the substrates dosage(s) in accordance with the respective Prescribing Information. ( 7.2 ) Certain CYP1A2, CYP3A, P-gp or UGT1A1 Substrates : Avoid concomitant use with these substrates for which minimal concentration changes may lead to serious toxicities. If concomitant use cannot be avoided, decrease the substrates dosage(s) in accordance with the respective Prescribing Information.

At a glance

Brand name: Rezurock
Active substance: belumosudil mesylate
Route: Oral
Dosage form: Tablet
Applicant: Kadmon Pharms LLC
Status: Prescription
FDA approval: 16 Jul 2021
Application: NDA214783-001

Indications

( 1 )

Warnings and precautions

Embryo-Fetal Toxicity : Can cause fetal harm. Advise females of reproductive potential of the potential risk to a fetus and to use effective contraception. ( 5.1 , 8.1 , 8.3 )

5.1Embryo-Fetal Toxicity Based

Interactions

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary Based

on findings from animal studies and the mechanism of action [see Clinical Pharmacology (12.1) ] , REZUROCK can cause fetal harm when administered to pregnant women. There are no available human data on REZUROCK use in pregnant women to evaluate for a drug-associated risk. In animal reproduction studies, administration of belumosudil to pregnant rats and rabbits during the period of organogenesis resulted in adverse developmental outcomes, including alterations to growth, embryo-fetal mortality, and embryo-fetal malformations at maternal exposures (AUC) approximately ≥1.4 (rat) and ≥0.08 (rabbit) times the human exposure (AUC) at the recommended dose (see Data ) .

Advise pregnant women and females of reproductive potential of the potential risk to the fetus. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2 to 4% and 15 to 20%, respectively. Data Animal data Embryo-fetal development studies were conducted in rats with administration of belumosudil to pregnant animals during the period of organogenesis at oral doses of 25, 50, 150, and 300 mg/kg/day in a pilot study and doses of 15, 50, and 150 mg/kg/day in a pivotal study.

In the pilot study, maternal toxicity and embryo-fetal developmental effects were observed. Maternal toxicity (reduced body weight gain) occurred at 150 and 300 mg/kg/day doses. Increased post-implantation loss occurred at 50 and 300 mg/kg/day. Fetal-malformations were observed at ≥50 mg/kg/day and included absence of anus and tail, omphalocele, and dome shaped head. The exposure (AUC) at 50 mg/kg/day in rats is approximately 1.4 times the human exposure at the recommended dose of 200 mg.

In an embryo-fetal developmental study in rabbits, pregnant animals administered oral doses of belumosudil at 50, 125, and 225 mg/kg/day during the period of organogenesis resulted in maternal toxicity and embryo-fetal developmental effects. Maternal toxicity (body weight loss and mortality) was observed at doses ≥125 mg/kg/day. Embryo-fetal effects were observed at doses ≥50 mg/kg/day and included spontaneous abortion, increased post-implantation loss, decreased percentage of live fetuses, malformations, and decreased fetal body weight.

Malformations included those in the tail (short), ribs (branched, fused or deformed), sternebrae (fused), and neural arches (fused, misaligned, and deformed). The exposure (AUC) at 50 mg/kg/day in rabbits is approximately 0.08 times the human exposure at the recommended dose of 200 mg.

Adverse reactions

The most common (≥20%) adverse reactions, including laboratory abnormalities, are infections, asthenia, nausea, diarrhea, dyspnea, cough, edema, hemorrhage, abdominal pain, musculoskeletal pain, headache, phosphate decreased, gamma glutamyl transferase increased, lymphocytes decreased, and hypertension. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact Kadmon Pharmaceuticals, LLC at 1-800-633-1610 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical Trial Experience

Because clinical trials are conducted under widely variable conditions, adverse reaction rates observed in clinical trials of a drug cannot be directly compared with rates of clinical trials of another drug and may not reflect the rates observed in practice. Chronic Graft versus Host Disease In two clinical trials (Study KD025-213 and Study KD025-208), 83 adult patients with chronic GVHD were treated with REZUROCK 200 mg once daily [see Clinical Studies (14.1) ] .

The median duration of treatment was 9.2 months (range 0.5 to 44.7 months). Fatal adverse reaction was reported in one patient with severe nausea, vomiting, diarrhea and multi-organ failure. Permanent discontinuation of REZUROCK due to adverse reactions occurred in 18% of patients. The adverse reactions which resulted in permanent discontinuation of REZUROCK in >3% of patients included nausea (4%). Adverse reactions leading to dose interruption occurred in 29% of patients.

The adverse reactions leading to dose interruption in ≥2% were infections (11%), diarrhea (4%), and asthenia, dyspnea, hemorrhage, hypotension, liver function test abnormal, nausea, pyrexia, edema, and renal failure with (2% each). The most common (≥20%) adverse reactions, including laboratory abnormalities, were infections, asthenia, nausea, diarrhea, dyspnea, cough, edema, hemorrhage, abdominal pain, musculoskeletal pain, headache, phosphate decreased, gamma glutamyl transferase increased, lymphocytes decreased, and hypertension.

Table 2 summarizes the nonlaboratory adverse reactions. Table 2: Nonlaboratory Adverse Reactions in ≥10% Patients with Chronic GVHD Treated with REZUROCK Adverse Reaction REZUROCK 200 mg once daily (N=83) All Grades (%) Grades 3–4 (%) Infections and infestations Infection (pathogen not specified) infection with an unspecified pathogen includes acute sinusitis, device related infection, ear infection, folliculitis, gastroenteritis, gastrointestinal infection, hordeolum, infectious colitis, lung infection, skin infection, tooth infection, urinary tract infection, wound infection, upper respiratory tract infection, pneumonia, conjunctivitis, sinusitis, respiratory tract infection, bronchitis, sepsis, septic shock. 53 16 Viral infection includes influenza, rhinovirus infection, gastroenteritis viral, viral upper respiratory tract infection, bronchitis viral, Epstein-Barr viremia, Epstein-Barr virus infection, parainfluenzae virus infection, Varicella zoster virus infection, viral infection. 19 4 Bacterial infection includes cellulitis, Helicobacter infection, Staphylococcal bacteremia, catheter site cellulitis, Clostridium difficile colitis, Escherichia urinary tract infection, gastroenteritis Escherichia coli, Pseudomonas infection, urinary tract infection bacterial. 16 4 General disorders and administration site conditions Asthenia includes fatigue, asthenia, malaise. 46 4 Edema includes edema peripheral, generalized edema, face edema, localized edema, edema. 27 1 Pyrexia 18 1 Gastrointestinal Nausea includes nausea, vomiting. 42 4 Diarrhea 35 5 Abdominal pain includes abdominal pain, abdominal pain upper, abdominal pain lower. 22 1 Dysphagia 16 0 Respiratory, thoracic and mediastinal Dyspnea includes dyspnea, dyspnea exertional, apnea, orthopnea, sleep apnea syndrome. 33 5 Cough includes cough, productive cough. 30 0 Nasal congestion 12 0 Vascular Hemorrhage includes contusion, hematoma, epistaxis, increased tendency to bruise, conjunctival hemorrhage, hematochezia, mouth hemorrhage, catheter site hemorrhage, hematuria, hemothorax, purpura. 23 5 Hypertension 21 7 Musculoskeletal and connective tissue Musculoskeletal pain includes pain in extremity, back pain, flank pain, limb discomfort, musculoskeletal chest pain, neck pain, musculoskeletal pain. 22 4 Muscle spasm 17 0 Arthralgia 15 2 Nervous system Headache includes headache, migraine. 21 0 Metabolism and nutrition Decreased appetite 17 1 Skin and subcutaneous Rash includes rash, rash maculo-papular, rash erythematous, rash generalized, dermatitis exfoliative. 12 0 Pruritus includes pruritus, pruritus generalized. 11 0 Table 3 summarizes the laboratory abnormalities in REZUROCK.

Table 3: Selected Laboratory Abnormalities in Patients with Chronic GVHD Treated with REZUROCK REZUROCK 200 mg once daily Grade 0–1 Baseline Grade 2–4 Max Post Grade 3–4 Max Post Parameter (N) (%) (%) Chemistry Phosphate decreased 76 28 7 Gamma Glutamyl Transferase increased 47 21 11 Calcium decreased 82 12 1 Alkaline Phosphatase increased 80 9 0 Potassium increased 82 7 1 Alanine Aminotransferase increased 83 7 2 Creatinine increased 83 4 0 Hematology Lymphocytes decreased 62 29 13 Hemoglobin decreased 79 11 1 Platelets decreased 82 10 5 Neutrophil Count decreased 83 8 4

Rezurock

Indications

Contraindications

Warnings and precautions

5.1Embryo-Fetal Toxicity Based

Interactions

At a glance

Two medicines in one question?

Rezurock

Indications

Contraindications

Warnings and precautions

5.1Embryo-Fetal Toxicity Based

Interactions

At a glance

Two medicines in one question?

7.1Effect of Other Drugs on

7.2Effect of

Pregnancy and breastfeeding

8.1Pregnancy Risk Summary Based

Adverse reactions

6.1Clinical Trial Experience

Composition

Official product information